Viral hepatitis is a mostly enterically transmitted liver disease caused by viral infection. The major transmission path of the disease is through ingestion; viral hepatitis is also transmitted through blood transfusion of virus-contaminated blood or blood products such as blood plasma.
Viral hepatitis is widespread around the world. For example, there are approximately thirty million viral hepatitis patients in China including an estimated number of nine million new patients each year and about one hundred million hepatitis B virus (HBV) carriers. Ten percent of the pregnant women in China are estimated to be HBV carriers. About one hundred thousand people in China die each year of liver cancer originated from liver diseases.
HBV infection is caused by hepatitis B virus, which is a 42-nm, double-stranded, and circular deoxyribonucleic acid (DNA) virus belonging to the class of Hepadnaviridae. HBV consists of a surface and a core. Four major polypeptide-encoding genes are in the HBV DNA genome: S (surface), C (core), P (polymerase), and X (transcriptional transactivating proteins). The S gene consists of three regions: the pre-S1 region, the pre-S2 region, and the region encoding the surface proteins. The surface proteins constitute the surface antigen (HBsAg). The C gene is divided into two (2) regions, the pre-core and the core region; the C gene encodes two (2) different proteins, the core antigen (HBcAg) and the e antigen (HBeAg).
HBsAg is found on the surface of the virus and produced in excess amount. HBsAg circulates in blood as a 22-nm spherical and tubular particle. HBsAg can be identified in serum 30-60 days after exposure to HBV and persists for variable period of time. Antibody to HBsAg (Anti-HBs) develops after a resolved infection and is responsible for long-term immunity.
Antibody to HBcAg (anti-HBc) develops in all types of HBV infections and persists indefinitely. IgM anti-HBc appears early in infection and persists for equal to or greater than six (6) months, and thus, it is a reliable marker for acute or recent HBV infection.
A third antigen, HBeAg may be detected in samples from patients with either acute or chronic HBV infection. The presence of HBeAg correlates with viral replication and high infectivity. Antibody to HBeAg (anti-HBe) develops in most HBV infections and correlates with the loss of replicating virus and lower infectivity.
Hepatitis B infection progresses with varying outcomes in the patient. Initially, acute infection in the liver causes the body to mount an immune response to get rid of the virus. The immune system tries to clear the virus by destroying HBV infected liver cells. In some people, the immune response succeeds so that the virus along with the infected liver cells are completely destroyed, and the patient makes a complete recovery. This is called the resolution of the disease. In other patients, however, the immune response to the infection is insufficient to get rid of the virus entirely for many months or years or not at all, and the immune response slowly destroys more and more infected liver cells as the virus spreads, which forms long-term infection. This slow but persistent destruction of liver cells by the immune system leads to fibrosis, cirrhosis and even liver cancer. People infected with HBV whose immune systems cannot get rid of the virus are referred to as the chronic HBV carriers. There are usually no obvious physical symptoms in patients of chronic HBV. Specific blood tests will reveal the presence of the virus, and the patient is also contagious via blood, birth, sex, needles, etc. Chronic HBV carriers can pass the virus to others.
U.S. Pat. No. 5,047,407 discloses a chemical compound having antiviral activities. The compound is (2R, cis)-4-amino-1-(2-hydroxmethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (also known as 3TC), and given the pharmacopoeia name lamivudine and selling in the market under the trade name Epivir by Glaxo SmithKline. Lamivudine is used for treatment and prophylaxis of viral infections.
Lamivudine is a nucleoside analogue that has a potent inhibitory effect on RNA-dependent DNA polymerase of HBV and human immunodeficiency virus (HIV). The antiviral effects of lamivudine on the suppression of HBV replication have been shown in vitro and in vivo. (Lai et al., N. Engl. J. Med. (1998), 339:61-68). Lamivudine accomplishes in most patients the suppression of viral replication as determined by the negativity of serum HBV-DNA, but the compound is much less effective in clearance of HBeAg within a short period of treatment. The ineffectiveness or reduced effect on HBeAg clearance may be attributed to the persistence of HBV covalently closed circular DNA (cccDNA) in hepatocyte nuclei; rapid relapse of HBV replication often occurs after withdrawal of lamivudine treatment. Prolonged lamivudine treatment has been proposed to solve the problem, and the seroconversion rate of HBeAg has been significantly improved.
When lamivudine is used for a prolonged period, it causes selection of lamivudine-resistant mutants of HBV and develops drug-resistance in patients, which casts a new challenge for the treatment regime. (Hussain et al., J. Viral. Hepat. (1999), 6:183-194; Balzarini et al., Biochem. Biophys. Res. Commun. (1996), 2:363-369). Lamivudine-resistant HBV mutants are primarily responsible for acute exacerbation and hepatic decompensation develop in patients during long-term lamivudine therapy. (Liaw et al., Hepatology (1999), 30:567-572).
Once the mutants are present and the patients develop drug-resistance, the physician faces a dilemma whether to stop or continue the treatment. In some cases, continuing treatment results in repeated exacerbation of hepatonecroinflammation, which leads to hepatic decompensation or cirrhosis; on the other hand, stopping treatment may result in re-activation of the wild type virus, which also leads to exacerbation of hepatonecroinflammation. Development of an antiviral treatment regime against the drug-resistance HBV mutants as well as wild type virus is pivotal for such patients.
The present invention provides an herbal pharmaceutical composition that is effective for treating viral infections, particularly, the composition is effective in treating viral hepatitis. The herbal pharmaceutical composition is also effective in treating lamivudine-resistant mutant HBV in vivo and in vitro. Additionally, the herbal pharmaceutical composition enhances the antiviral treatment effects of lamivudine and ameliorates the development of lamivudine-resistant HBV mutants caused by prolonged usage of Lamivudine.
The herbal pharmaceutical composition is named Yi-Gan-Kang (in Chinese, “Yi” means “second or B”; “Gan” means “liver”; “Kang” means “health”; collectively, “Yi-Gan-Kang” denotes “healthy liver devoid of HBV infection”), abbreviated as YGK.